title: Safety (toxicity), pharmacokinetics, immunogenicity, and impact on elements of the normal immune system of recombinant human IL-15 in rhesus macaques.
abstract: IL-15 uses the heterotrimeric receptor IL-2/IL-15Rβ and the γ chain shared with IL-2 and the cytokine-specific IL-15Rα. Although IL-15 shares actions with IL-2 that include activation of natural killer (NK) and CD8 T cells, IL-15 is not associated with capillary leak syndrome, activation-induced cell death, or with a major effect on the number of functional regulatory T cells. To prepare for human trials to determine whether IL-15 is superior to IL-2 in cancer therapy, recombinant human IL-15 (rhIL-15) was produced under current good manufacturing practices. A safety study in rhesus macaques was performed in 4 groups of 6 animals each that received vehicle diluent control or rhIL-15 at 10, 20, or 50 μg/kg/d IV for 12 days. The major toxicity was grade 3/4 transient neutropenia. Bone marrow examinations demonstrated increased marrow cellularity, including cells of the neutrophil series. Furthermore, neutrophils were observed in sinusoids of enlarged livers and spleens, suggesting that IL-15 mediated neutrophil redistribution from the circulation to tissues. The observation that IL-15 administration was associated with increased numbers of circulating NK and CD8 central and effector-memory T cells, in conjunction with efficacy studies in murine tumor models, supports the use of multiple daily infusions of rhIL-15 in patients with metastatic malignancies.
authors.affiliation: Center for Cancer Research, National Cancer Institute, Frederick, MD, USA. tawald@helix.nih.gov
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Waldmann
authors.forename: Enrico
authors.initials: E
authors.lastname: Lugli
authors.forename: Mario
authors.initials: M
authors.lastname: Roederer
authors.forename: Liyanage P
authors.initials: LP
authors.lastname: Perera
authors.forename: Jeremy V
authors.initials: JV
authors.lastname: Smedley
authors.forename: Rhonda P
authors.initials: RP
authors.lastname: Macallister
authors.forename: Carolyn K
authors.initials: CK
authors.lastname: Goldman
authors.forename: Bonita R
authors.initials: BR
authors.lastname: Bryant
authors.forename: Jean M
authors.initials: JM
authors.lastname: Decker
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Fleisher
authors.forename: H Clifford
authors.initials: HC
authors.lastname: Lane
authors.forename: Michael C
authors.initials: MC
authors.lastname: Sneller
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Kurlander
authors.forename: David E
authors.initials: DE
authors.lastname: Kleiner
authors.forename: John M
authors.initials: JM
authors.lastname: Pletcher
authors.forename: William D
authors.initials: WD
authors.lastname: Figg
authors.forename: Jason L
authors.initials: JL
authors.lastname: Yovandich
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Creekmore
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000276:immunology / Q000493:pharmacokinetics / Q000633:toxicity; D001777:Blood Coagulation / Q000187:drug effects; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D006801:Humans; D007167:Immunotherapy; D007262:Infusions, Intravenous; D019409:Interleukin-15 / Q000008:administration & dosage / Q000276:immunology / Q000493:pharmacokinetics / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008253:Macaca mulatta; D009369:Neoplasms / Q000276:immunology / Q000628:therapy; D009503:Neutropenia / Q000097:blood / Q000139:chemically induced; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000276:immunology / Q000493:pharmacokinetics / Q000633:toxicity
chemical_list: D000970:Antineoplastic Agents; D019409:Interleukin-15; D011994:Recombinant Proteins